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WO2016028391A9 - Spiropyrrolidines utiles en tant qu'inhibiteurs de mdm2 - Google Patents

Spiropyrrolidines utiles en tant qu'inhibiteurs de mdm2 Download PDF

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Publication number
WO2016028391A9
WO2016028391A9 PCT/US2015/037974 US2015037974W WO2016028391A9 WO 2016028391 A9 WO2016028391 A9 WO 2016028391A9 US 2015037974 W US2015037974 W US 2015037974W WO 2016028391 A9 WO2016028391 A9 WO 2016028391A9
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WO
WIPO (PCT)
Prior art keywords
chloro
phenyl
fluoro
methyl
spiro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/037974
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English (en)
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WO2016028391A2 (fr
WO2016028391A3 (fr
Inventor
Yi Chen
Qingjie DING (Jack)
Yang-sheng SUN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hudson Biopharma Inc
Original Assignee
Hudson Biopharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hudson Biopharma Inc filed Critical Hudson Biopharma Inc
Priority to CA2958193A priority Critical patent/CA2958193C/fr
Priority to ES15833638T priority patent/ES2959097T3/es
Priority to CN201580003250.3A priority patent/CN105829318B/zh
Priority to EP15833638.8A priority patent/EP3183255B1/fr
Priority to AU2015303959A priority patent/AU2015303959B2/en
Priority to JP2017529969A priority patent/JP6625638B2/ja
Publication of WO2016028391A2 publication Critical patent/WO2016028391A2/fr
Publication of WO2016028391A9 publication Critical patent/WO2016028391A9/fr
Publication of WO2016028391A3 publication Critical patent/WO2016028391A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to spiropyrrolidine compounds useful in treating diseases linked to the malfunction of p53 signal pathway such as cancer.
  • MDM2 is a negative regulatory protein of tumor suppressor protein p53.
  • p53 regulates cell cycle growth, apoptosis, senescence and functions as the guardian of the cellular genomic integrity in response to various cellular stresses including DNA damage, hypoxia and oncogene activation. It acts as one of the most important defense against the development of cancer.
  • MDM2 and P53 forms an auto-regulatory feedback control loop and MDM2 negatively regulates the functions of p53 through 1) direct binding to p53 and inhibits its ability to trans-activate p53 regulated genes; 2) mediating the ubiquitin dependent degradation of p53; 3) export of p53 out of the nucleus.
  • p53 can induce the expression of MDM2 gene and hence the MDM2 protein in cells. This feedback loop control insures in normal cells that MDM2 and p53 stay at a suitable low level.
  • MDM2 binds E2F through a conserved binding region as p53 and activates the E2F dependent transcription of cyclin A (Martin K., Nature, 1995, 375, 691-694; Strachan, G.D. et al, Journal of biological Chemistry, 2001, 456, 45677- 45685), suggesting that MDM2 inhibitors might also have the prospects to treat p53 mutated cells.
  • This invention describes the discovery of spiropyrrolidines (I) as inhibitors of MDM2/p53 interactions and provides useful agents for the treatment of diseases linked to the malfunction of p53 signal pathway including cancer and age related retinal macular degeneration.
  • the invented compounds herein have the general I formula of I where R 1 , R 2, R 3, R 4, R 7 , A, B and X are defined in the following.
  • the current invention also relates to pharmaceutical compositions that comprise one or more compounds of the invention, a pharmaceutically acceptable salt or pro-drug and a pharmaceutically acceptable carrier or excipient.
  • the present invention further relates to a method for the treatment of cancer, in particular the treatment of leukemia, solid tumors and age related retinal macular degeneration disorders. DESCRIPTION OF THE INVENTION
  • the present invention describes the discovery of spiropyrrolidine derivatives of general structural formula I which are MDM2 inhibitors and are useful as anticancer agents and can also be used for the treatment of age related retinal macular degeneration disorders as well as other diseases linked to the malfunction of p53 signal pathway.
  • A are halogens and are independently selected from Cl and F and B are independently selected from Cl, H and F;
  • R 1 is aryl, substituted aryl, heteroaryl and substituted heteroaryl;
  • R 2 is hydrogen or it is a carbon-carbon bond with either X, R 3 or R 4 ;
  • R 3 and R 4 are independently selected from H, lower alkyl and substituted lower alkyls, cycloalkyls, substituted cycloalkyls, alkenyls, substituted alkenyls, alkyns, substituted alkyns, or they together can form a 3, 4, or 5 membered ring or one ofh m an form a C-C bond with R 2 ;
  • X is independently selected from F, CN, and , where R5 and R6 are independently selected from hydrogen and F; and
  • R7 is halogen and is selected independently from Cl, Br and F.
  • R 3 and R 4 form a ring, it can be, in embodiments applicable to all formulas I– IV, a carbocyclic ring.
  • R 3 and R 4 link back to via a bond that is R 2
  • the result can be, in embodiments applicable to all formulas I– IV, a carbocyclic ring, such as a 3– 5 membered ring.
  • R is independently selected from groups of halogen, hydroxyl, hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, cyano, amino, substituted amino, sulfonylamino, substituted sulfonylamino, aminosulfonyl, substituted aminosulfonyl, hydroxycarbonyl, lower alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, carbonylamino, substituted carbonylamino, amidino, substituted amidino, guanidino, substituted guanidino, tetrazoles, substituted tetrazoles and can independently substitute any single position or multiple positions of the aryl /heteroaryl ring and preferably not to exceed three positions; Or when the substitution occurs at two adjacent positions, it can form a five or six membered hetero ring;
  • R 5 and R 6 are independently selected from hydrogen and F.
  • R 1 is
  • R is independently selected from groups of halogen, hydroxyl, hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, cyano, amino, substituted amino, sulfonylamino, substituted sulfonylamino, aminosulfonyl, substituted aminosulfonyl, hydroxycarbonyl, lower alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, carbonylamino, substituted carbonylamino, amidino, substituted amidino, guanidino, substituted guanidino, tetrazoles, substituted tetrazoles and can independently substitute any single position or multiple positions of the aryl /heteroaryl ring and preferably not to exceed three positions; Or when the substitution occurs at two adjacent positions, it can form a five or six
  • R 1 and R 7 are as described above; A is independently selected from Cl, F, and Br; B is selected from F, H; and R 3 and R 4 are independently selected from H, and methyl.
  • R 1 is
  • R is independently selected from groups of halogen, hydroxyl, hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, cyano, amino, substituted amino, sulfonylamino, substituted sulfonylamino, aminosulfonyl, substituted aminosulfonyl, hydroxycarbonyl, lower alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, carbonylamino, substituted carbonylamino, amidino, substituted amidino, guanidino, substituted guanidino, tetrazoles, substituted tetrazoles and can independently substitute any single position or multiple positions of the aryl /heteroaryl ring and preferably not to exceed three positions; Or when the substitution occurs at two adjacent positions, it can form a five or six
  • R is independently selected from groups of halogen, hydroxyl, hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, cyano, amino, substituted amino, sulfonylamino, substituted sulfonylamino, aminosulfonyl, substituted aminosulfonyl, hydroxycarbonyl, lower alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, carbonylamino, substituted carbonylamino, amidino, substituted amidino, guanidino, substituted guanidino, tetrazoles, substituted tetrazoles and can independently substitute any single position or multiple positions of the aryl /heteroaryl ring and preferably not to exceed three positions; Or when the substitution occurs at two adjacent positions, it can form a five or six
  • R 2 is H
  • R 3 and R 4 together form a 3, 4, or 5 membered aliphatic ring, such as a cyclopropyl ring
  • R 5 and R 6 are both H.
  • racemic in the listing below emphasizes that a racemate of that particular compound is subject matter which may be claimed.
  • the designation“chiral” emphasizes a single enantiomer that can be synthesized either by asymmetric synthesis or alternatively by separation of a racemate by chiral technology(such as chiral HPLC, or chiral supercritical fluid chromatography) or by resolution of a racemate by common chemistry method.
  • the compounds are:
  • compositions comprising of an effective amount of any one or more of the above claimed compounds, a pharmaceutically acceptable salt or pro-drug or a pharmaceutically acceptable carrier or excipient.
  • the current invention is also directed to a method for treating solid tumors, leukemia and retinal macular degeneration diseases by administering an effective amount of a compound of formula I, its salts or pro-drugs, to a patient.
  • Halogen means F, Cl, Br or I. Preferred halogens are F and Cl.
  • Lower alkyl means a linear chain or branched, substituted or unsubstituted, saturated aliphatic hydrocarbon having 1-6, preferably 1-4 carbon atoms.
  • Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl etc.
  • IC 50 means the concentration of a particular compound that inhibits 50% of a specific measured activity.
  • Cycloalkyl refers to a non-aromatic, partially or completely cyclic aliphatic hydrocarbon containing 3 to 7 atoms. Cyclopropyl, cyclobutyl, cyclopental and cyclohexyl are some of the examples. [0079] Substituted means that the substitution can occur at one or more positions and, unless otherwise indicated, the substituents at each substitution site are independently selected from the specific options.
  • Pro-drug refers to a compound that may be converted under physiological conditions or by solvolysis to any of the compounds of formula I.
  • a pro-drug may be inactive when administered but is converted to an active compound of formula I in vivo.
  • Pharmaceutically acceptable means pharmacologically acceptable to a subject to which a particular compound is administered.
  • Pharmaceutically acceptable salt means an acid-addition salts or base- addition salts which retain the biological effectiveness and properties of the compounds of formula I.
  • Typical acid-addition salts include those that are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid and those that are derived from organic acids like formic acid, methane sulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, p-toluene sulfonic acid, salicylic acid and so on.
  • Samples of base derived salts include those derived from ammonium, sodium, potassium and so on.
  • Heteroaryl groups are aromatic groups having 5-10 atoms, one or two rings and contain one or more hetero atoms.
  • Hetero atoms refer to N, O, S, P.
  • Aryls refer to aromatic groups carrying 5-10 atoms and consisting of 1 or 2 rings. Examples of aryl groups include phenyl, naphthyl.
  • Alkenyl means a linear or branched, substituted or unsubstituted aliphatic unsaturated hydrocarbon carrying 2-6, preferably 2-4, carbon atoms and containing double bonds.
  • an "effective amount" of a therapeutic agent will be recognized by clinicians but includes an amount effective to treat, reduce, alleviate, ameliorate, eliminate or prevent one or more symptoms of the condition sought to be treated, or alternately, the condition sought to be avoided, or to otherwise produce a clinically recognizable favorable change in the condition or its effects.
  • the compounds of the invention can be prepared according to the following schemes.
  • the key intermediates 1, 2 and 5 could be prepared as described in scheme I and Scheme II. Condensation of amine with aldehyde gave desired imine 1 and 2.
  • the amine can also be used in the salt form ( HCl or trifluoroacetic acid salt). In those cases, a base like triethylamine was used to release the free amine.
  • enantiomerically pure diasteromers of I can be obtained through general chemistry technique.
  • racemic mixture of I could be separated by chiral HPLC, chiral superfluid HPLC or by common resolution methods such as the application of chiral base or chiral acid through crystallization.
  • Desired isomers may also be prepared through asymmetric synthesis by employing chiral auxiliary, chiral ligand (for a reference, see Antonchick et al, Nature Chemistry, 2010, 2, 735-740).
  • All of the compounds can be used, generally in an effective amount, to treat proliferative disorders such as cancer.
  • An effective amount of one or more of the compounds in the art can be formulated and delivered to patients through oral, parenteral, patch, spray and other well-known art.
  • the compounds discovered in the art can also be used together with other agents for combination therapy. Without being bound by theory, it is believed that the agents in the art can be particularly useful where the p53 protein is not mutated to a dysfunctional form and/or its signaling pathways still function.
  • An effective amount here may vary from, without limitation, a dosage of 1mg to 1500mg/Kg per day for a patient with an average body weight of 70Kg depending on any specific case.
  • Formulation of a certain compound generally means the employment of some carriers, excipient and other material to make the dosage work more efficiently.
  • a subject for such treatment can be any animal subject to such proliferative disorders, such as humans. Examples
  • Ethyl 4-(2-aminoacetamido)-3-methoxybenzoate (758.75 mg, 2.5 mmol), Et 3 N (303 mg, 3 mmol) and 4-fluoro-3,3-dimethylbutanal (295 mg, 2.5 mmol) were suspended in MTBE (Aldrich, 7 mL) and the mixture was stirred at rt overnight. Wash with water and the organic layer was dried with sodium sulfate . Removal of solvent under reduced pressure gave a white solid. 800 mg, 99%.
  • the second component from the column was desired product. 220 mg, 20%.
  • Example 70 Preparation of (1- fluoromethyl-cyclopropyl)-acetonitrile [00242] To a stirred solution of methane sulfonic acid 1-cyanomethyl- cyclopropylmethyl ester (6.0 g, 31.7 mmol) in THF (10 mL) was added tetra-n- butylammonium fluoride (1N in THF, 46.5mL, 46.5 mmol) dropwise at room temperature over 1 h. After the end of the addition, the resulting solution was held at reflux for 1 h. The mixture was gradually cooled to room temperature over 20 min and then diluted with water (50 mL).
  • reaction mixture was diluted with water (1mL) and then acidified to pH 6 with 55% citric acid (3mL). After stirring at room temperature for 30 min, the mixture was filtered, and the collected solids were washed with water (10 mL) and dried to give an off-white solid.
  • Test compounds (12.34 uM stock in DMSO) were diluted three fold in series in DMSO and 2 ul per well were added into 384-well polypropylene plates (Matrix) in triplicates.
  • GST-tag full length MDM2 22 nM, 30.8 ul/well
  • Assay Buffer 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM DTT and 0.2 mg/ml BSA
  • Assay Buffer 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM DTT and 0.2 mg/ml BSA
  • 72 nM biotin p53 peptide Biotin-Aca- SQETFSDLWKLLPEN-OH
  • All the tested compounds could be dissolved in DMSO at 10 -2 M (as stock solution). All compounds except Reference compound were dissolved well after being diluted in culture medium to 10 -4 M. Reference compound was in a suspension state after being diluted in medium to 10 -4 M and even being ultra-sonicated at 60 ⁇ for 30 min but in a solution state at 33.33 ⁇ M. The compounds were diluted at 9 3- fold serial concentrations beginning at the initial concentration of 10 ⁇ M (i.e., the highest final concentration to treat the cells).
  • the detailed drug dilution protocol is: Add 5 ⁇ L stock solution (10 -2 M) into 495 ⁇ L medium, transfer 125 ⁇ L of the resulting solution (100 ⁇ M) into 250 ⁇ L medium, and repeat this till the 9 th resulting concentration of 15.2 nM. Pipet 20 ⁇ L of each drug dilution into cell plates.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne des spiropyrrolidines (I) utiles en tant qu'inhibiteurs de l'interaction MDM2/p53 et procurant des agents utiles dans le traitement de maladies, telles que le cancer et la dégénérescence maculaire qui touche la rétine. Les composés de l'invention ont la formule générale (I). L'invention concerne également des compositions pharmaceutiques qui comprennent au moins un composé selon l'invention, un sel pharmaceutiquement acceptable ou un pro-médicament et/ou un support ou excipient pharmaceutiquement acceptable.
PCT/US2015/037974 2014-08-18 2015-06-26 Spiropyrrolidines utiles en tant qu'inhibiteurs de mdm2 Ceased WO2016028391A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA2958193A CA2958193C (fr) 2014-08-18 2015-06-26 Spiropyrrolidines utiles en tant qu'inhibiteurs de mdm2
ES15833638T ES2959097T3 (es) 2014-08-18 2015-06-26 Espiropirrolidinas como inhibidores de MDM2
CN201580003250.3A CN105829318B (zh) 2014-08-18 2015-06-26 作为mdm2抑制剂的螺吡咯烷
EP15833638.8A EP3183255B1 (fr) 2014-08-18 2015-06-26 Spiropyrrolidines utiles en tant qu'inhibiteurs de mdm2
AU2015303959A AU2015303959B2 (en) 2014-08-18 2015-06-26 Spiropyrrolidines as MDM2 inhibitors
JP2017529969A JP6625638B2 (ja) 2014-08-18 2015-06-26 Ｍｄｍ２阻害薬としてのスピロピロリジン

Applications Claiming Priority (2)

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US201462038548P 2014-08-18 2014-08-18
US62/038,548 2014-08-18

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WO2016028391A2 WO2016028391A2 (fr) 2016-02-25
WO2016028391A9 true WO2016028391A9 (fr) 2016-03-31
WO2016028391A3 WO2016028391A3 (fr) 2016-05-12

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US (1) US9701685B2 (fr)
EP (1) EP3183255B1 (fr)
JP (1) JP6625638B2 (fr)
CN (1) CN105829318B (fr)
AU (1) AU2015303959B2 (fr)
CA (1) CA2958193C (fr)
ES (1) ES2959097T3 (fr)
WO (1) WO2016028391A2 (fr)

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WO2023056069A1 (fr) 2021-09-30 2023-04-06 Angiex, Inc. Conjugués agent de dégradation-anticorps et leurs procédés d'utilisation

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EP3183255C0 (fr) 2023-07-05
US9701685B2 (en) 2017-07-11
CA2958193A1 (fr) 2016-02-25
WO2016028391A2 (fr) 2016-02-25
JP2017525768A (ja) 2017-09-07
EP3183255B1 (fr) 2023-07-05
EP3183255A4 (fr) 2018-01-10
AU2015303959A1 (en) 2017-03-09
JP6625638B2 (ja) 2019-12-25
EP3183255A2 (fr) 2017-06-28
CA2958193C (fr) 2024-02-27
AU2015303959B2 (en) 2019-10-31
US20150322076A1 (en) 2015-11-12
WO2016028391A3 (fr) 2016-05-12
ES2959097T3 (es) 2024-02-20
CN105829318A (zh) 2016-08-03
CN105829318B (zh) 2018-10-02

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